Cocaine abuse and addiction endure as serious problems in our society. The scientific community retains the challenge of defining mechanisms of cocaine addiction and of identifying potential treatment strategies. Over the past five years, researchers have successfully identified alterations in the functioning of endogenous brain reward circuits following acute cocaine administration. In addition, they have begun to discover cellular and molecular mechanisms responsible for cocaine's effects on neurotransmitter systems that play pivotal roles in mediating the positive reinforcing effects of this psychomotor stimulant. The past two years have witnessed considerable advancement in our understanding of relatively persistent alterations in neurotransmitter function which accompany repeated cocaine administration and withdrawal. It is now clear that the mechanisms underlying cocaine intoxication and addiction involve a cascade of events and interactions between neurotransmitter systems. Identifying such interactions looms as the next challenge to those interested in the neurobiology of cocaine addiction. Although the mesoaccumbens and mesocortical dopamine systems have been most frequently implicated in the rewarding effects of cocaine and in the induction of sensitization (reverse tolerance) to its psychomotor stimulant effects, both serotonin and amino acid transmitters also play important roles in regulating the effects of cocaine within these systems. Serotonin systems apparently contribute to an aversive component of cocaine's subjective effects whereas excitatory amino acid (EAA) receptors appear to be necessary for the induction of sensitization during repeated cocaine administration. The present studies seek to identify the physiological mechanisms by which these transmitter systems interact with mesoaccumbens and mesocortical dopamine neurons and their postsynaptic targets. Extracellular single cell recording and microiontophoretic techniques will be use to address 5 specific aims. Two aims will investigate acute effects of cocaine. We will determine: 1) the role of serotonin neurons in modulating the influences of EAAs and GABA (an inhibitory amino acid transmitter) on mesoaccumbens and mesocortical dopamine neurons within the rat ventral tegmental area; and 2) the roles of EAA afferents from the medial prefrontal cortex (mPFC), ventral subiculum and basolateral amygdala in cocaine effects on accumbens neurons. Three aims will examine the effects of repeated cocaine administration and withdrawal and will emphasize: 3) the possible roles of Dl dopamine, GABA, and EAA receptors in altering the activity of mesoaccumbens dopamine neurons 4) the roles of EAA, GABA and 5-HT receptors in altering the activity of nucleus accumbens neurons; and 5) possible alterations in the effects of cocaine on mPFC neurons. The hypothesis guiding these investigations is that acute and repeated cocaine administration not only directly influence dopamine neurons and their postsynaptic targets, but also alter their activity by interacting with other regulatory systems. It is anticipated that these experiments will provide valuable basic information regarding time-dependent alterations in reward relevant neurons following cocaine use. Such information may aid in the development of treatment strategies for cocaine addiction.